The present invention relates to a novel artificial medical material and more particularly to a medical material which comprises a hydrogel having superior properties not found in conventional natural or synthetic polymers.
In most of the tissues of a living body there is embedded a large amount of water, and it is as already often pointed out that this water has a very important significance [see Tatsuro Yamaguchi, "Ohyo Biseibutsu Kenkyu Seminar 1," Gihodo, p. 55 (1979); Hisashi Uedaira, Hyomen, 13, 297 (1975); W. Drost-Hansen, Federation Proc., 30, 1539 (1971); and J. D. Andrade et al., Trans. Am. Soc. Artif. Intern. Organs, 19, 1 (1973)].
Therefore, in the selection of prosthesis, a hydrous high polymer (hydrogel) is now expected to be superior in biocompatibility [see Tatsuzo Tanabe et al., "Jinko Kekkan," Nankodo, p. 56 (1977) and S. D. Bruck, J. Biomed. Mater. Res., 7, 387 (1973)].
Furthermore, in the case of using synthetic or natural high polymers as medical materials, thrombosis on the contact surface between those materials and blood has long been recognized as a serious problem of artificial valve, vascular graft, artificial kidney, liver, pancreas and catheter, and efforts have been continued for obtaining a material which is difficult to behave as a foreign body against blood, that is, a material which is difficult to form thrombus caused by blood destruction [see Tatsuzo Tanabe, Gekashinryo, 8, 1441 (1966) and Tatsuzo Tanabe et al., Jinko Zoki, 1, 17 (1972)].
A hydrogel does less damage to the tissues and an increase in its water content results in improvement in its antithrombosis, therefore it is expected as a medical material. However, all of conventional hydrogels have a serious defect such that they are inferior in mechanical strength. For this reason, their use is extremely limited [see Tatsuzo Tanabe et al., "Jinko Kekkan," Nankodo, p. 56 (1977); Tatsuzo Tanabe, Jinko Zoki, 5, 245 (1976); S. D. Bruck, J. Biomed. Mater. Res., 7, 387 (1973); H. Singh et al., J. Sci. Ind. Res., 39, March, 162 (1980); and J. D. Andrade et al., Trans. Am. Soc. Artif. Intern. Organs, 19, 1 (1973)].
There have been proposed a number of hardening means (for improving mechanical strength) involving treating a hydrogel (or gelling component) with formaldehyde, glutaraldehyde, terephthalaldehyde, or hexamethylenediamine. However, it is well known that since those treatments employ the chemicals harmful to tissue, thus treated hydrogel causes various troubles. For example, a vascular graft (Ivalon), obtained by cross-linking polyvinyl alcohol with formalin, has been broken. Moreover it has been pointed out that if such cross-linked product of a polyvinyl alcohol with formalin is used for augmentation mammoplasty, it contracts enormously. At present, it is considered that those chemicals cannot be used [see Tatsuzo Tanabe et al., "Jinko Zoki Shiryo Shusei," Life Science Center, p. 330 and 88 (1976); J. R. Lewis, Plast. & Reconstr. Surg., 35, 51 (1965); and Yasuo Muto, Nippon Rinsho Geka-Shi, 26, 25 (1965)].
Moreover, as a result of application of such chemical treatment, the superior characteristics of hydrogel and largely diminished.
As the sole method for hardening a weak hydrogel without application of such chemical treatment, irradiation method is now suggested [see N. A. Peppas et al., J. Biomed. Mater. Res., 4, 423 (1977) and H. Singh et al., J. Sci. Ind. Res., 39, (March), 162 (1980)]. But this method requires a special equipment and its effect is not so remarkable. Therefore, its practical application is difficult. Besides, there have been reported many examples wherein the superior features of a hydrogel are lost during radiation.
The present invention provides a prosthesis that is superior in mechanical strength and biocompatibility, prepared without the foregoing chemical treatment or irradiation.
The present invention further provides a thromboresistant material, which is obtained by embedding a medicine (anticoagulant) in the hydrogel of the present invention to improve the antithrombosis.
As the method of preventing the coagulation of blood by using a medicine, there has long been adopted a method wherein heparin (heparin calcium, heparin sodium, or the like) is administered by intravenous, subcutaneous or intramuscular injection, or a oral adminstration of Warfarin potassium (3-.alpha.-phenyl-.beta.-acetyl-ethyl-4-hydroxycoumarin potassium), Bishydrocoumarin (Dicumarol), Indan-1,3-dione, Ethylbiscoumacetate (Tromexan), Phenprocoumon (Liquamar), Acenocoumarin (Sintrom), Phenindione (Danilone, Dindevan, Hedulin), Diphenadione (Dipaxin), Anisindione (Miradon), or the like. However, the administration to an allergic subject for a long period is likely to cause asthma, urticaria, skin itching, rhinitis, epiphora, pyrexia, alopecia, spontaneous fracture, polyporous bone, hematoma with topalgia, interdental bleeding, epistases, vomiting and diarrhea. In general, moreover, the patient continues to encounter the dangerous hemorrhagic diathesis. Therefore, those methods are by no means preferable.
On the basis of the idea that it is not necessary to spread anticoagulant in whole cardiovascular system, there have been proposed many attempts to let a very small amount of anticoagulant be present on the surface of the medical material. For example, an anticoagulant (heparin, hirudin, antithrombin), a blood platelet agglutination inhibitor (adenyl cyclase, prostaglandin E, methylxanthine), and a fibrinolytic activator (urokinase, streptokinase) are applied to the surface of the medical material, or adsorbed through an ionic functional group, or immobilized by covalent bond [see Tatsuzo Tanabe Jinko Zoki 5, 247 (1976) and Jinko Zoki, 1, 17 (1972)]. However, in the application or adsorption method, the anticoagulant, etc. easily comes off the said contact surface and therefore the available period is short [see Tatsuzo Tanabe, Kyobu Geka, 25, 347 (1972)]. In the covalent-bond method, the anticoagulant is often damaged during the chemical reaction, and the introduced functional group may cause tissue reaction; besides, the anticoagulant thus immobilized cannot function as expected. This method is not useful [see Tatsuzo Tanabe, "Jinko Kekkan," Nankodo, p. 73 and 57 (1977); Yoji Imai, Kobunshi, 21, 570 (1972); Yuichi Mori et al., Kobunshi, 22, 614 (1973); H. Tanzawa et al., Trans. Am. Soc. Artif. Intern. Organs, 19, 188 (1973); Hiroshi Tanzawa, Geka Shinryo, 20, 2 (1978); Shigeo Shimizu et al., Kagaku Keizai, 24, (2) 19 (1977); Yuichi Mori, "Jinko Zoki Shiryo Shusei," Life Science Center, p. 117 (1976); and Hiroshi Tanzawa, Kagaku Kogyo, 1260 (1974)].
In order to avoid such drawbacks, there has been reported an attempt of embedding the anticoagulant into the medical material [see H. Tanzawa et al., Trans. Am. Soc. Artif. Intern. Organs, 19, 188 (1973)]. But it is often pointed out that the anticoagulant which has not been immobilized (entrapped) by means of any chemical bond is released, and the available period is considered to be 5 to 8 hours, or 5 days or so at most. With a view to decreasing the release (flow-out) rate of the anticoagulant, it has also been tried to chemically treat the surface of the material (or anticoagulant) with glutaraldehyde. In this case, however, it is necessary to take care not to damage the anticoagulant, for example, the treatment must be conducted at a pH of 4 to 5.5 and at a reaction temperature of 59.degree. to 85.degree. C. Therefore, it is impossible to expect much of the effect of the treatment.
The present invention dispenses with the operation using chemical reagents or radiation as in the conventional methods and hence does not damage at all the anticoagulant used, and embeds the anticoagulant firmly in a medical hydrogel, thereby providing a medical material capable of releasing the anticoagulant over a long period on the portion requiring an anticoagulating action (the contact surface between the medical material and blood).
The present invention uses a polyvinyl alcohol as a material for preparing an antithrombotic hydrogel. As the method of gelling an aqueous polyvinyl alcohol, there have already been proposed various methods. But, as summarized below, all of those methods are not satisfactory.
(1) By air-drying an aqueous polyvinyl alcohol solution, there is obtained a wet or dry film, which, however, is merely a weak film inferior in water resistance and having no stiffness in water and applied to only limited uses (see Japanese Patent Publication No. 9523/1965).
(2) Also by the method herein an acid is added to an aqueous suspension containing polyvinyl alcohol and tetraethyl silicate, followed by air-drying, there merely is obtained a similar film to that obtained in the above (1). In this connection, there has also been proposed the application of freeze-drying after addition of the acid; but the film thereby obtained is rather deteriorated in its strength to the extent that the molding operation for the film is scarcely feasible (see Japanese Patent Publications Nos. 30358/1980 and 11311/1980).
(3) It is well known that an aqueous polyvinyl alcohol solution forms a gel during cobalt 60 (.gamma.-ray) radiation. In this case, however, special facilities (irradiation facilities) are absolutely necessary and the irradiation cost is high; besides, the resultant gel is weak and often requires another hardening (secondary hardening treatment). Therefore, the gel obtained by this method is difficult to be utilized except in special uses where a highly viscous liquid (or a soft gel) is desired, such as an artificial vitreous (intraeyeball filling liquid) (see J. Material Sci., 1974, 1815 and Japanese Patent Laying Open Print No. 55647/1975).
(4) Also, it has long been well known that an aqueous polyvinyl alcohol, when mixed with boric acid (or an aqueous solution thereof) or borax (or an aqueous solution thereof) (Note: borax=sodium tetraborate decahydrate), gels immediately. But the gel thus obtained is weak, has fluidity, and is torn to pieces immediately when merely picked with finger tips; therefore, its shape is difficult to be retained [see J. Am. Chem. Soc., 60, 1045 (1938) and French Pat. No. 743942 (1933)]. Besides, this borax gel easily collapses at a pH value not higher than 8 though it can exist under an alkaline condition, and therefore it is difficult to utilize it as a medical material, and thus it is of little value.
(5) There also have been proposed a number of gelling methods for polyvinyl alcohol by using phenols such as phenol, naphthol and Congo Red or amino compounds or metallic compounds such as titanium, chromium and zirconium, but all of which involve the same drawbacks as in the above (4) (see Nippon Kagaku Zasshi, 72, 1058 (1951) and Japanese Patent Publication No. 9523/1965 and No. 23204/1965).
(6) Also well known is the gelation of polyvinyl alcohol by using cross-linking agents or copolymer components such as aldehydes, dialdehydes, unsaturated nitriles, diisocyanates, trimethylolmelamine, epichlorohydrin, bis-(.beta.-hydroxyethyl)sulfone, polyacrylic acid, dimethylolurea and maleic anhydride; however, these methods require chemical reagents and a strong gel having a high water content is not obtainable [see Textile Res. J., (3), 189 (1962) and British Pat. No. 742,900 (1958)].
(7) Aqueous polyvinyl alcohols are known to form hydrogels by allowing them to stand at a low temperature not higher than 40.degree. C., particularly beween 0.degree. C. and 18.degree. C. [see Kominami et al., Kobunshi Kagaku, 12, 218 (1955); Maeda et al., Kobunshi Kagaku, 13, 193 (1956) and Kogyo Kagaku Zasshi, 59, 809 (1956)]. However, the gel formed at room temperature is fragile like agar and carrageenan, and it dissolves by vigorous stirring, mixing with water or warming [see Kominami et al., Kobunshi Kagaku, 12, 218 (1955) and Takahashi and Sakurada, Kobunshi Kagaku, 13, 502 (1956)]. It is also well well known that low temperatures are desirable for obtaining polyvinyl alcohol gels, and there are known examples wherein the gelation is carried out at low temperatures of 18.degree. C. and further 0.degree. C. or even at a temperature below 0.degree. C. [see Maeda et al., Kobunshi Kagaku, 13, 193 (1956), Japanese Patent Publication No. 12854/1972 and Takahashi et al., Polymer J., 6, 103 (1974)]. In any case, however, the resultant gel is weak (or a viscous liquid) like ager, carrageenan and jelly, is very sticky and poor in water resistance, swells remarkably in water and softens, is partially dissolved out into water and the remainder becomes paste-like. Moreover, in warm water at 40.degree.-50.degree. C., the gel easily gets out of shape and is dispersed and dissolved in water. Thus, it is difficult to recognize its value as a medical material.
(8) A spongy product obtained by formalizing a polyvinyl alcohol has also been well known, but it is not stable within a tissue, and along with its decomposition and deterioration, it exerts a harmful influence upon its surroundings. In recent years, therefore, its use has been extremely limited [see Tatsuzo Tanabe et al., "Jinko Zoki Shiryo Shusei," Life Science Center, p. 330 (1976); ibid. p. 88 (1976); and J. R. Lewis, Plast, & Reconstr. Surg., 35, 51 (1965)].
(9) Also known is a method wherein a small amount of a polyvinyl alcohol is added to an aqueous solution of a water-soluble high polymer having gelling ability such as agarose, agar, albumin, alginate, curdlan, carrageenan, casein, CMC (sodium carboxymethyl cellulose), furcellaran, gelatin, methyl cellulose, pectin, starch, tamarind gum, xanthan gum, tragacanth gum, or guar gum, and the resulting solution is allowed to cool or immersed in a gelling agent-containing bath (coagulation bath) or subjected to freeze-drying [see Fragrance Journal, 2, (7) 68 (1974) and Japanese Patent Publications Nos. 25210/1981 and 25211/1981]. Even according to this method, there merely is obtained a weak and water-soluble viscous liquid or dry water-soluble powder (freeze-dried powder).